Natural experiences cause changes in the brain. Some changes represent actual storage of new information, whereas others are changes in the way the brain processes ongoing experience. Deficits or abnormalities in the way the brain responds to experience may contribute to disorders of learning, memory, cognition and brain homeostasis. This research is directed at understanding the molecular, cellular and integrative mechanisms that determine how the brain responds to new experiences. A key aspect of the research is a strategic focus on the adult zebra finch as a model. Zebra finches are colonial animals and communicate via a number of vocalizations, including learned song. Adults discriminate among individuals based on the songs they hear them singing, and also respond to tape-recorded birdsong. When an isolated bird first encounters the sound of a particular birdsong, the bird adopts a distinct "listening" posture and several things happen in a part of the brain analogous to human auditory cortex (called the auditory lobule). Intracellular signaling enzymes are activated, transcription of various genes goes up, and specific proteins begin to accumulate. Recent results suggest that these changes may underlie a functional shift in the way the brain processes or stores information. If another song is presented when these molecular changes are in full swing, the bird more quickly forms a memory of the second song. The research goals for the next period are to answer four questions about these phenomena. 1) are the observed molecular correlates actually necessary for learning and memory? We will test this by cannula-directed infusion of pharmacological and antisense "knockdown" agents. 1) What intracellular events mark the onset of the period of enhanced learning? Proteomic techniques (DICE, MALDI-ToF) will be used to compare the auditory lobule from "learning" vs "habituated" birds. 1) What genes are activated during enhanced learning? Here we take advantage of new microarray reagents that are being developed under a sister project, the Songbird Neurogenomics Initiative 1) What neurotransmitter(s) signals trigger the molecular/cellular response in the auditory lobule? In collaboration with Profs. Gold and Sweedler, we will test specific hypotheses using in vivo microdialysis, analytical chemistry and targeted injections of pharmacological agents.